A native interactor scaffolds and stabilizes toxic Ataxin-1 oligomers in SCA1

C. A. Lasagna-Reeves, M. W C Rousseaux, M. J. Guerrero-Munoz, J. Park, P. Jafar-Nejad, R. Richman, N. Lu, U. Sengupta, A. Litvinchuk, H. T. Orr, Rakez Kayed, H. Y. Zoghbi

Research output: Contribution to journalArticle

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Abstract

Recent studies indicate that soluble oligomers drive pathogenesis in several neurodegenerative proteinopathies, including Alzheimer and Parkinson disease. Curiously, the same conformational antibody recognizes different disease-related oligomers, despite the variations in clinical presentation and brain regions affected, suggesting that the oligomer structure might be responsible for toxicity. We investigated whether polyglutamine-expanded Ataxin1, the protein that underlies spinocerebellar ataxia type 1, forms toxic oligomers and, if so, what underlies their toxicity. We found that mutant ATXN1 does form oligomers and that oligomer levels correlate with disease progression in the Atxn1154Q/+ mice. Moreover, oligomeric toxicity, stabilization and seeding require interaction with Capicua, which is expressed at greater ratios with respect to ATXN1 in the cerebellum than in less vulnerable brain regions. Thus, specific interactors, not merely oligomeric structure, drive pathogenesis and contribute to regional vulnerability. Identifying interactors that stabilize toxic oligomeric complexes could answer longstanding questions about the pathogenesis of other proteinopathies.

Original languageEnglish (US)
Pages (from-to)1-46
Number of pages46
JournaleLife
Volume4
Issue numberMAY
DOIs
StatePublished - May 19 2015

Fingerprint

Spinocerebellar Ataxias
Poisons
Oligomers
Scaffolds
Brain
Cerebellum
Parkinson Disease
Toxicity
Disease Progression
Alzheimer Disease
Antibodies
Ataxin-1
Drive
Stabilization
polyglutamine

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Lasagna-Reeves, C. A., Rousseaux, M. W. C., Guerrero-Munoz, M. J., Park, J., Jafar-Nejad, P., Richman, R., ... Zoghbi, H. Y. (2015). A native interactor scaffolds and stabilizes toxic Ataxin-1 oligomers in SCA1. eLife, 4(MAY), 1-46. https://doi.org/10.7554/eLife.07558

A native interactor scaffolds and stabilizes toxic Ataxin-1 oligomers in SCA1. / Lasagna-Reeves, C. A.; Rousseaux, M. W C; Guerrero-Munoz, M. J.; Park, J.; Jafar-Nejad, P.; Richman, R.; Lu, N.; Sengupta, U.; Litvinchuk, A.; Orr, H. T.; Kayed, Rakez; Zoghbi, H. Y.

In: eLife, Vol. 4, No. MAY, 19.05.2015, p. 1-46.

Research output: Contribution to journalArticle

Lasagna-Reeves, CA, Rousseaux, MWC, Guerrero-Munoz, MJ, Park, J, Jafar-Nejad, P, Richman, R, Lu, N, Sengupta, U, Litvinchuk, A, Orr, HT, Kayed, R & Zoghbi, HY 2015, 'A native interactor scaffolds and stabilizes toxic Ataxin-1 oligomers in SCA1', eLife, vol. 4, no. MAY, pp. 1-46. https://doi.org/10.7554/eLife.07558
Lasagna-Reeves CA, Rousseaux MWC, Guerrero-Munoz MJ, Park J, Jafar-Nejad P, Richman R et al. A native interactor scaffolds and stabilizes toxic Ataxin-1 oligomers in SCA1. eLife. 2015 May 19;4(MAY):1-46. https://doi.org/10.7554/eLife.07558
Lasagna-Reeves, C. A. ; Rousseaux, M. W C ; Guerrero-Munoz, M. J. ; Park, J. ; Jafar-Nejad, P. ; Richman, R. ; Lu, N. ; Sengupta, U. ; Litvinchuk, A. ; Orr, H. T. ; Kayed, Rakez ; Zoghbi, H. Y. / A native interactor scaffolds and stabilizes toxic Ataxin-1 oligomers in SCA1. In: eLife. 2015 ; Vol. 4, No. MAY. pp. 1-46.
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